PHENOTYPIC HETEROGENEITY OF NEUTROPHILS: NEW ANTIMICROBIC CHARACTERISTICS AND DIAGNOSTIC TECHNOLOGIES

Introduction. Neutrophils are the most numerous subpopulation of leukocytes circulating in the blood; they constitute the first line of defence of the innate link of the immune system.

Aim. To generalize basic concepts about phenotypic and functional heterogeneity of neutrophils.

General findings. According to contemporary concepts, this type of blood cells performs not only antimicrobial functions, but also participates in capture and destruction of various microorganisms, including such processes as phagocytosis and intracellular degradation, degranulation and formation of extracellular neutrophilic traps after the detection of microorganisms. Neutrophils are considered to be a phenotypically heterogeneous pool of blood cells featuring a significant functional variability. Under pathological conditions, they can differentiate into discrete subpopulations with va rious phenotypic and functional characteristics. They are capable of interaction with macrophages, natural killers, dendritic and mesenchymal stem cells, B and T lymphocytes or platelets. In addition, neutrophils exhibit vector properties with respect to cancerous tumours. They possess a high morphological and functional variability, being modulators of both inflammation and active triggers of immune responses. A search for molecular markers able to efficiently differentiate neutrophil phenotypes and establish the degree of their diagnostic specificity for various pathologies is of a particular importance.

1. de Oliveira S., Rosowski E.E., Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nature Reviews Immunology. 2016; 16(6): 378. DOI: 10.1038/nri.2016.49

2. Wang J., Hossain M., Thanabalasuriar A., et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science. 2017; 358(6359): 111–6. DOI: 10.1126/science.aam9690

3. Jones H. R., Robb C. T., Perretti M., et al. The role of neutrophils in inflammation resolution. Seminars in immunology. Academic Press. 2016; 289(2): 137–45. DOI: 10.1016/j.smim.2016.03.007

4. Kaur M., Singh D. Neutrophil chemotaxis caused by chronic obstructive pulmonary disease alveolar macrophages: the role of CXCL8 and the receptors CXCR1/CXCR2. Journal of Pharmacology and Experimental Therapeutics. 2013; 347(1): 173–80. DOI: 10.1124/jpet.112.201855

5. Andryukov B.G., Somova L.M., Drobot Ye.I., Matosova Ye.V. Antimicrobial strategies of neutrophils in infectious diseases. Klinicheskaya labjratornaya diagnоstika. 2016; 12(61): 825–33 (In Rissian). DOI: 10.18821/0869-2084- 2016-61-12-825-833

6. Wirths S., Stefanie Bugl S., Kopp H.-G. Steady-state neutrophil homeostasis is a demand-driven process. Cell Cycle. 2013; 12(5): 709–10. DOI: 10.4161/cc.23859

7. Cain D.W., Ueda Y., Holl T.M., et al. A comparison of “steady-state” and “emergency” granulopoiesis: evidence of a single pathway for neutrophil production. The Journal of Immunology, 2009; 182 (1): 87–95.

8. Cowland J.B., Borregaard N. Granulopoiesis and granules of human neutrophils. Immunological reviews. 2016; 273(1): 11–28. DOI: 10.1111/imr.12440/

9. Kanamaru R., Ohzawa H., Miyato H., et al. Neutrophil Extracellular Traps Generated by Low Density Neutrophils Obtained from Peritoneal Lavage Fluid Mediate Tumor Cell Growth and Attachment. J Vis Exp. 2018; 138. DOI: 10.3791/58201

10. Witko-Sarsat V., Pederzoli-Ribeil M., Hirsch E., et. al. Regulating neutrophil apoptosis: new players enter the game. Trends Immunol. 2011; 32: 117–24. DOI: 10.1016/j.it.2011.01.001

11. Luo D., McGettrick H.M., Stone P.C., et al. The roles of Integrins of Human Neutrophils after their migration through endothelium into intestinal matrix. PLOS One. 2015; 10(2): e0118593. DOI: 10.1371/journal.pone.0118593

12. Steinberg B.E., Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Science’s STKE. 2007; 2007(379): pe11. DOI: 10.1126/stke.3792007pe11

13. Marini O., Costa S., Bevilacqua D., et al. Mature CD10+ and immature CD10-neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood. 2016; 04: 713206. DOI: 10.1182/blood-2016-04-713206

14. Dopico X. C., Evangelou M., Ferreira R. C., et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nature communications. 2015; 6: 7000. DOI: 10.1038/ncomms8000

15. Kim M. H., Yang D., Kim M., et al. A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis. Scientific reports. 2017; 7: 39804. DOI: 10.1038/srep39804

16. Garlichs C.D., Eskafi S., Cicha I., et al. Delay of neutrophil apoptosis in acute coronary syndromes. Journal of leukocyte biology. 2004; 75(5): 828–35. DOI: 10.1189/jlb.0703358

17. Summers C., Singh N. R., White J. F., et al. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax. 2014; thoraxjnl-2013-204742. DOI: 10.1136/ thoraxjnl-2013-204742

18. Matosova Е.V., Andryukov B.G. Morphofunctional characteristics of protective mechanisms of neutrophils against bacterial infections and their contribution in pathogenesis of pro-inflammatory. Gematologiya i transfuziologiya. 2017; 62(4): 223–9 (In Russian). DOI: 10.18821/0234-5730-2017-62-4-223-229

19. Jorgensen I., Rayamajhi M., Miao E.A. Programmed cell death as a defence against infection. Nature reviews immunology. 2017; 17(3): 151. DOI: 10.1038/ nri.2016.147

20. Jorgensen I., Lopez J.P., Laufer S.A., et al. IL-1β, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. European journal of immunology. 2016; 46(12): 2761–6. DOI: 10.1002/ eji.201646647

21. Rodriguez F.M., Novak I.T.C. What about the neutrophil’s phenotypes? Hematol Med Oncol. 2017; 2: 1–6. DOI: 10.15761/HMO.1000130

22. Adrover J.M., Nicolás-Ávila J.A., Hidalgo A. Aging: a temporal dimension for neutrophils. Trends Immunol. 2016; 37: 334–45. DOI: 10.1016/j.it.2016.03.005

23. Brinkmann V., Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012; 198(5): 773–83. DOI: 10.1083/ jcb.201203170

24. Silvestre-Roig C., Hidalgo A., Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood. 2016 127:2173-2181 DOI: 10.1182/blood-2016-01-688887

25. Horckmans M., Ring L., Duchene J., et al. Neutrophils orchestrate postmyocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J. 2017; 38: 187–97. DOI: 10.1093/eurheartj/ehw002

26. Hellebrekers P., Vrisekoop N., Koenderman L. Neutrophil phenotypes in health and disease. Eur J Clin Invest. 2018; 48 Suppl 2: e12943. DOI: 10.1111/ eci.12943

27. Sagiv J.Y., Voels S., Granot Z. Isolation and Characterization of Low- vs HighDensity Neutrophils in Cancer. Methods Mol Biol. 2016; 1458: 179–93. DOI: 10.1007/978-1-4939-3801-8_13

28. Kuhns D.B., Priel D.A.L., Chu J., et al. Isolation and Functional Analysis of Human Neutrophils. Curr Protoc Immunol. 2015; 111: 7.23.1–16. DOI: 10.1002/0471142735.im0723s111

29. Deniset J.F., Kubes P. Neutrophil heterogeneity: Bona fide subsets or polarization states? J Leukoc Biol. 2018; 103(5): 829–38. DOI: 10.1002/JLB.3RI0917- 361R

30. Mortaz E., Alipoor S.D., Adcock I.M., et al. Update on Neutrophil Function in Severe Inflammation. Front Immunol. 2018; 9: 2171. DOI: 10.3389/ fimmu.2018.02171

31. Bekkering S., Torensma R. Another look at the life of a neutrophil. World J Hematol 2013; 2(2): 44–58. DOI: 10.5315/wjh.v2.i2.44

32. Nesterova I.V., Kolesnikova N.V., Chudilova G.A., et al. The new look at neutrophilic granulocytes: rethinking old dogmas. Part 1. Infekciya i immunitet. 2018; 7(3): 219–30 (In Russian). DOI: 10.15789/2220-7619-2017-3-219- 230

33. Galdiero M. R., Bonavita E., Barajon I., et al. Tumor associated macrophages and neutrophils in cancer. Immunobiology. 2013; 218(11): 1402–10. DOI: 10.1016/j.imbio.2013.06.003

34. Lai Guan Ng. Neutrophil: A mobile fertilizer J Exp Med. 2019; 216(1): 4–6. DOI: 10.1084/jem.20182059

35. Mishalian I., Granot Z., Fridlender Z.G. The diversity of circulating neutrophils in cancer. Immunobiology. 2017; 222(1): 82–8. DOI: 10.1016/j. imbio.2016.02.001

36. McCracken J.M., Allen L.A.H. Regulation of Human Neutrophil Apoptosis and Lifespan in Health and Disease. J Cell Death. 2014; 7: 15–23. DOI: 10.4137/ JCD.S11038

37. Je Lin Sieow, Sin Yee Gun, Siew Cheng Wong The Sweet Surrender: How Myeloid Cell Metabolic Plasticity Shapes the Tumor Microenvironment. Front Cell Dev Biol. 2018; 6: 168. DOI: 10.3389/fcell.2018.00168

38. Sionov R.V., Fridlender Z.G., Granot Z. The multifaceted roles neutrophils play in the tumor microenvironment. Cancer Microenviron. 2014; 8(3):125–58.

39. Coffelt S.B., Wellenstein M.D., de Visser K.E. Neutrophils in cancer: neutral no more. Nature Reviews Cancer. 2016; 16(7): 431. DOI: 10.1038/nrc.2016.52/

40. Swierczak A., Mouchemore K.A., Hamilton J.A., Anderson R.L. Neutrophils: important contributors to tumor progression and metastasis. Cancer Metastasis Rev. 2015; 34(4): 735–51. DOI: 10.1007/s10555-015-9594-9

41. Kurashige M., Kohara M., Ohshima K., et al. Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation. Commun Biol. 2018; 1: 131.

42. Sawanobori Y., Ueha S., Kurachi M., et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood. 2008; 111(12): 5457–66. DOI: 10.1182/blood-2008-01-136895

43. Granot Z., Henke E., Comen E.A., et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell. 2011; 20(3): 300–14.

44. Shaul M.E., Levy L., Sun J., et al. Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology. 2016; 5(11): e1232221. DOI: 10.1080/2162402X.2016.1232221

45. Skendros P., Mitroulis I., Ritis K. Autophagy in Neutrophils: From Granulopoiesis to Neutrophil Extracellular Traps. Front Cell Dev Biol. 2018; 6: 109.

46. Rosales C. Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Front Physiol. 2018; 9: 113. DOI: 10.3389/fphys.2018.00113

47. Uribe-Querol E., Rosales C. Neutrophils in Cancer: Two Sides of the Same Coin. J Immunol Res. 2015; 2015: 983698. DOI: 10.1155/2015/983698

48. Sagiv J. Y., Michaeli J., Assi S., et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell reports. 2015; 10(4): 562–73. DOI: 10.1016/j.celrep.2014.12.039

49. Lee W., Ko S.Y., Mohamed M.S., et al. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med. 2019; 216(1): 176–94. DOI: 10.1084/jem.20181170

50. Granot Z, Jablonska J. Distinct Functions of Neutrophil in Cancer and Its Regulation. Mediators Inflamm. 2015; 701067. DOI: 10.1155/2015/701067

51. Lopez-Lago M.A., Posner S., Thodima V.J., et al. Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene, 2013; 32(14): 1752–60.

52. Hong C.W. Current Understanding in Neutrophil Differentiation and Heterogeneity. Immune Netw. 2017; 17(5): 298–306.

53. Liu Y., Yue Hu, Gu F., et al. Phenotypic and clinical characterization of low density neutrophils in patients with advanced lung adenocarcinoma. Oncotarget. 2017; 8(53): 90969–78. DOI: 10.18632/ oncotarget. 18771

54. Carmona-Rivera C., Kaplan M.J. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin. Immunopathol. 2013; 35: 455–63. DOI: 10.1007/s00281-013-0375-7

55. Wright H. L., Makki F. A., Moots R. J., et al. Low-density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signaling. Journal of leukocyte biology. 2017; 101(2): 599–611. DOI: 10.1189/jlb.5A0116-022R.

56. Hallett M. B. The Neutrophil: Cellular Biochemistry and Physiology. CRC Press; 2017.

57. Erpenbeck L., Schön M.P. Neutrophil extracellular traps: protagonists of cancer progression? Oncogene. 2017; 36(18): 2483. DOI: 10.1038/onc.2016.406

58. Porta C., Sica A., Riboldi E. Tumor-associated myeloid cells: new understandings on their metabolic regulation and their influence in cancer immunotherapy. FEBS J. 2018; 285(4): 717–33. DOI: 10.1111/febs.14288

59. Khadge S., Sharp J.G., McGuire T.R., et al. Immune regulation and anticancer activity by lipid inflammatory mediators. Int Immunopharmacol. 2018; 65: 580–92. DOI: 10.1016/ j. intimp.2018.10.026